This application is a 371 of PCT/JP00/08669 filed Dec. 7, 2000.
The present invention relates to novel substituted guanidine derivatives, prodrugs thereof or pharmaceutically acceptable salts of the derivatives or prodrugs, pharmaceutical uses of the derivatives, prodrugs or salts, and a process for production of the derivatives, prodrugs or salts. The compounds of the present invention inhibit the sodium/proton (Na+/H+) exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused by the acceleration of the sodium/proton (Na+/H+) exchange transport system, for example, hypertension, arrhythmia, angina pectoris, cardiac hypertrophy, cardiac insufficiency, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion [e.g. cardiac ischemic reperfusion-injury, acute renal failure, or disorder induced by surgical treatment such as organ transplantation or percutaneous transluminal coronary angioplasty (PTCA)], diseases caused by hyperplasia such as hyperplasia of fibroblast, hyperplasia of smooth muscle cells or hyperplasia of mesangium cells, which diseases are, for example, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, glomerular nephrosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications or restenosis after PTCA, or diseases caused by endotherial cell injury.
As substituted guanidine derivatives having inhibitory effect on the sodium/proton (Na+/H+) exchange transport system, there may be exemplified the compounds disclosed in Japanese Patent Unexamined Publication Nos. 7-10839, 8-208602, 10-237073 and 9-291076 and International Publication No. WO 9961414.
In recent years, there has been reported the degeneration of nerve cells in mice which have underwent gene mutation relating to the sodium/proton (Na+/H+) exchange transport system (for instance, Cell, 91, 139-148 (1997)). It has been revealed that among known substituted guanidine derivatives having inhibitory effect on the sodium/proton (Na+/H+) exchange transport system, such as those exemplified above, there are substituted guanidine derivatives having an undesirable effect on nerve cells, i.e., substituted guanidine derivatives capable of degenerating nerve cells. It is suggested that such degeneration of nerve cells is likely to cause various neuropathies. Therefore, there is desired the development of a Na+/H+ exchange transport system inhibitor reduced in such an effect on nerve cells.
The present inventors earnestly investigated in order to achieve the above object, and consequently found that a compound represented by the general formula (1), a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug (if necessary, the compound, prodrug or salt is hereinafter abbreviated as the present inventive compound in some cases) has an excellent inhibitory effect on the sodium/proton (Na+/H+) exchange transport system and exhibits only markedly lessened side effects on the nervous system, in particular, the central nervous system. That is, the present invention relates to the following.
[1]
A compound represented by the formula (1): 
wherein R is a substituted or unsubstituted benzene ring, a fused polycyclic hydrocarbon ring which is substituted or unsubstituted, a monocyclic heterocyclic ring which is substituted or unsubstituted, or a polycyclic heterocyclic ring which is substituted or unsubstituted;
A and E are independently a single bond or a substituted or unsubstituted lower alkylene group (one or more of the xe2x80x94CH2xe2x80x94 groups of said lower alkylene group may be replaced by one or more groups, which may be the same or different and are selected from the groups consisting of a group represented by the formula: xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1)xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94, a benzene ring and a cycloalkane ring (one or more of the xe2x80x94CH2xe2x80x94 groups in said cycloalkane ring may be replaced by one or more groups, which may be the same or different and are represented by the formula: xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R2)xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94) and any two adjacent atoms of said lower alkylene group may form a double bond or a triple bond);
G is a single bond or a group represented by the formula: xe2x80x94Oxe2x80x94 or xe2x80x94N(R11)xe2x80x94;
Y is a group represented by the formula: xe2x80x94SO3H, xe2x80x94PO3H2, xe2x80x94CO2H or 
xe2x80x83provided that G is a single bond when Y is a group represented by the formula: xe2x80x94PO3H2 or xe2x80x94CO2H;
R1, R11 and R2 are independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted acyl group, or a group represented by the formula: xe2x80x94C(xe2x95x90O)N(R5)R6, 
xe2x80x83or xe2x80x94S(O)nR3.
R3 and R3a are independently a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a substituted or unsubstituted heterocyclic group;
R5, R6, R7 and R8 are independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted acyl group, or R5 and R6, or R7 and R8 may bind to each other to form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered saturated cyclic amino group which may contain other heteroatom(s) in the ring and may be substituted by one or more substituted or unsubstituted alkyl groups, hydroxyl groups or xe2x80x94OR4b groups;
R4, R4a and R4b are independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted heterocyclic group or xe2x80x94SO3H; and
n is an integer of 0, 1 or 2, or
a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug.
[2]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1], wherein E is a single bond.
[3]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1] or [2], wherein A is a single bond, and G is a group represented by the formula: xe2x80x94Oxe2x80x94.
[4]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1], [2] or [3], wherein Y is a group represented by the formula: xe2x80x94SO3H.
[5]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1] or [2], wherein Y is a group represented by the formula: xe2x80x94PO3H2.
[6]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1], [4] or [5], wherein each of E and G is a single bond.
[7]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1] or [4], wherein each of E, A and G is a single bond.
[8]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [2], [3], [4], [5], [6] or [7], wherein R is a substituted or unsubstituted indole.
[9]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [2], [3], [4], [5], [6] or [7], wherein R is a substituted or unsubstituted benzene.
[10]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [2], [3], [4], [5], [6] or [7], wherein R is 1H-indene, 1,2-dihydronaphthalene, 6,7-dihydro-5H-benzocycloheptene, 2,3-dihydro-1H-benz[b]azepine or 2,3-dihydro-benz[b]oxepine, which may be substituted or unsubstituted.
[11]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [2], [3], [4], [5], [6] or [7], wherein R is a substituted or unsubstituted 6,7-dihydro-5H-benzocycloheptene.
[12]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [2], [3], [4], [5], [6] or [7], wherein R is 1,3,4,5-tetrahydro-benz[cd]indole or 3,4,5,6-tetrahydro-1H-cyclohepta[cd]indole, which may be substituted or unsubstituted.
[13]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [2], [3], [4], [5], [6] or [7], wherein R is 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline, 2,3-dihydro-pyrrolo[1,2,3-de][1,4]-benzoxazine, 2,3-dihydro-1H-pyrrolo[1,2,3-de]-quinoxaline, 4,5-dihydro-pyrrolo[3,2,1-hi]indole, 4,5,6,7-tetrahydro-pyrrolo[3,2,1-jk][1]benzazepine, 5,6,7,8-tetrahydro-4H-pyrrolo[3,2,1-kl][1]benzazocine, 4,5,7,8-tetrahydro-pyrrolo[3,2,1-kl]benz[e][1,4]-oxazocine or 4,5,7,8-tetrahydro-pyrrolo[3,2,1-kl]benzo[e][1,4]diazocine, which may be substituted or unsubstituted.
[14]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [2], [3], [4], [5], [6] or [7], wherein R is 5,6,7,8-tetrahydro-4H-pyrrolo[3,2,1-kl][1]benzazocine, 4,5,7,8-tetrahydro-pyrrolo[3,2,1-kl]benz[e][1,4]oxazocine or 4,5,7,8-tetrahydro-pyrrolo[3,2,1-kl]benzo[e][1,4]diazocine, which may be substituted or unsubstituted.
[15]
A prodrug or pharmaceutically acceptable salt of a compound according to any one of the above items [1] to [14], wherein Y is a group represented by the formula: xe2x80x94SO3R40, xe2x80x94P(xe2x95x90O)(OH)(OR41), xe2x80x94P(xe2x95x90O)(OR42)(OR43) or xe2x80x94C2R44 wherein R40, R41, R42 R43 and R44 are independently a substituted or unsubstituted alkyl group.
[16]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to the above item [1], which is selected from the group consisting of 2-[[[amino(imino)methyl]amino]carbonyl]-1-methyl-4-(trifluoromethyl)-1H-indol-6-yl hydrogen sulfate, 2-[[[amino(imino)methyl]amino]carbonyl]-1-methyl-4-(trifluoromethyl)-1H-indol-7-yl hydrogen sulfate, [2-[[[amino(imino)methyl]amino]carbonyl]-1-methyl-4-(trifluoromethyl)-1H-indol-6-yl]-methylphosphonic acid and 3-[2[[[amino(imino)methyl]amino]carbonyl]-4-chloro-1H-indol-1-yl]-1-propanesulfonic acid.
[17]
A pharmaceutical composition comprising a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of the above items [1] to [16].
[18]
A pharmaceutical composition for inhibiting the sodium/proton exchange transport system which comprises a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of the above items [1] to [16].
[19]
A pharmaceutical composition for the treatment or prophylaxis of hypertension, arrhythmia, angina pectoris, cardiac insufficiency, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion, diseases caused by excessive cell proliferation, or diseases caused by endothelial cell injury, which comprises a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of the above items [1] to [16].
[20]
A compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of the above items [1] to [16], which is for use as an active ingredient of a pharmaceutical composition.
[21]
Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of the above items [1] to [16] in the manufacture of a pharmaceutical composition for inhibiting the sodium/proton exchange transport system.
[22]
Use of a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of the above items [1] to [16] in the manufacture of a pharmaceutical composition for the treatment or prophylaxis of hypertension, arrhythmia, angina pectoris, cardiac insufficiency, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion, diseases caused by excessive cell proliferation, or diseases caused by endothelial cell injury.
[23]
A method for inhibiting the sodium/proton exchange transport system which comprises administering a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of the above items [1] to [16] to an object for the administration, in an effective amount.
[24]
A method for treating or preventing hypertension, arrhythmia, angina pectoris, cardiac insufficiency, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion, diseases caused by excessive cell proliferation, or diseases caused by endothelial cell injury, which comprises administering a compound, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug according to any one of the above items [1] to [16] to an object for the administration, in an effective amount.
[25]
A process for producing a compound represented by the formula (1): 
wherein Y, G, A, R and E are as defined in the above item [1], a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug, which comprises reacting a compound represented by the formula (2): 
wherein Y, G, A, R and E are as defined in the above item [1], and L is a hydroxyl group or a leaving group which may be substituted by a nucleophilic reagent, with guanidine.
A prodrug or pharmaceutically acceptable salt of a compound represented by the formula (1): 
wherein E is a single bond; wherein R is a substituted or unsubstituted indole; wherein the group represented by xe2x80x94C(O)NHC(NH)NH2 in the formula (1) is attached to 2-position thereof;
A is a single bond or a substituted or unsubstituted lower alkylene group (one or more of the xe2x80x94CH2xe2x80x94 groups of said lower alkylene group may be replaced by one or more groups, which may be the same or different and are selected from the group consisting of a group represented by the formula: xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R1)xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94, a benzene ring and a cycloalkane ring (one or more of the xe2x80x94CH2xe2x80x94 groups in said cycloalkane ring may be replaced by one or more groups, which may be the same or different and are represented by the formula: xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R2)xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94) and any two adjacent atoms of said lower alkylene group may form a double bond or a triple bond);
G is a single bond or a group represented by the formula: xe2x80x94Oxe2x80x94 or xe2x80x94N(R11)xe2x80x94;
R1, R11 and R2 are independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted acyl group; or a prodrug of said compound, or a pharmaceutically acceptable salt of said compound or prodrug;
Y is a group represented by the formula: xe2x80x94SO3R40, xe2x80x94P(xe2x95x90O)(OH)(OR41), or xe2x80x94P(xe2x95x90O)(OR42)(OR43) wherein R40, R41, R42, and R43 are independently a substituted or unsubstituted alkyl group.
[26]
A process for producing a compound which may be replaced by the formula (12): 
wherein G, A, R and E are as defined above, a prodrug thereof or a pharmaceutically acceptable salt of the compound or prodrug, which comprises reacting a compound represented by the formula (3): 
wherein A, R and E are as defined in the above item [1], and G is a group represented by the formula xe2x80x94Oxe2x80x94 or xe2x80x94N(R11)xe2x80x94 wherein R11 is as defined in the above item [1], with sulfur trioxide (SO3) or a complex thereof.
Compounds having inhibitory effect on the Na+/H+ exchange transport system exhibit a variety of pharmacokinetics, depending on their structures. For reducing side effects and the like, drugs capable of being distributed in desirable sites of action but not in undesirable sites are preferable. The compound of the present invention has a property of being hardly distributed in, in particular, the central nervous system in the case of its general administration such as oral administration or intravenous administration. Therefore, it is conjectured that the compound of the present invention has little side effect on central nervous system when used as a therapeutic or prophylactic agent for hypertension, arrhythmia, angina pectoris, cardiac insufficiency, cardiac hypertrophy, diabetes mellitus, organ disorders associated with ischemia or ischemic reperfusion [e.g. cardiac ischemic reperfusion-injury, acute renal failure, or disorder induced by surgical treatment such as organ transplantation or percutaneous transluminal coronary angioplasty (PTCA)], diseases caused by hyperplasia such as hyperplasia of fibroblast, hyperplasia of smooth muscle cells or hyperplasia of mesangium cells, which diseases are, for example, atherosclerosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, glomerular nephrosclerosis, organ hypertrophy, prostatic hypertrophy, diabetic complications or restenosis after PTCA, or diseases caused by endotherial cell injury.
The various groups in the present invention are explained below. Unless otherwise specified, the following explanation applies to the case where each of the groups is a portion of another group.
The terms xe2x80x9cfused polycyclic hydrocarbon ringxe2x80x9d, xe2x80x9cmonocyclic heterocyclic ringxe2x80x9d and xe2x80x9cpolycyclic heterocyclic ringxe2x80x9d for R mean rings, respectively, formed by the conversion of two of the hydrogen atoms of the corresponding ring explained below to bonds. The specific names of the rings for R are described in the above items [6] to [12]. They also mean rings, respectively, formed by the conversion of two of the hydrogen atoms of a corresponding ring to bonds.
The heterocyclic group includes monocyclic heterocyclic groups and polycyclic heterocyclic groups. The terms xe2x80x9cmonocyclic heterocyclic groupxe2x80x9d and xe2x80x9cpolycyclic heterocyclic groupxe2x80x9d mean groups formed by the conversion of one of the hydrogen atoms of the monocyclic heterocyclic ring or polycyclic heterocyclic ring, respectively, explained below to a bond.
The term xe2x80x9cfused polycyclic hydrocarbon ring groupxe2x80x9d means a group formed by the conversion of one of the hydrogen atoms of the fused polycyclic hydrocarbon ring explained below to a bond.
The term xe2x80x9csaturated heterocyclic groupxe2x80x9d means a group formed by the conversion of one of the hydrogen atoms of the saturated heterocyclic ring explained below to a bond.
The saturated heterocyclic ring includes the undermentioned 3- to 8-membered, saturated, heterocyclic and monocyclic rings containing 1 to 4 nitrogen atoms, 3- to 8-membered, saturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two oxygen atoms, and 3- to 8-membered, saturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two sulfur atoms.
The fused polycyclic hydrocarbon ring includes, for example, fused polycyclic hydrocarbon ring groups of 16 or less carbon atoms, such as indene, naphthalene, azulene, fluorene, phenalene, phenanthrene, anthracene, acephenanthrylene, 1,2-dihydronaphthalene, 6,7-dihydro-5H-benzocycloheptene, benzocyclooctene, etc. Preferable examples of the fused polycyclic hydrocarbon ring are indene, naphthalene and 6,7-dihydro-5H-benzocycloheptene.
The monocyclic heterocyclic ring includes 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing 1 to 4 nitrogen atoms, 3- to 8-membered, saturated, heterocyclic and monocyclic rings containing 1 to 4 nitrogen atoms, 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing an oxygen atom, 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing one or two sulfur atoms, 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two oxygen atoms, 3- to 8-membered, saturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two oxygen atoms, 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two sulfur atoms, 3- to 8-membered, saturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two sulfur atoms, and 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing an oxygen atom and one or two sulfur atoms.
The 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing 1 to 4 nitrogen atoms include, for example, pyrrole, pyrroline, pyridine, dihydropyridine, imidazole, pyrazole, imidazoline, pyrazine, pyrimidine, pyridazine, pyrazole, triazole and tetrazole. Preferable examples thereof are pyrrole, pyridine, imidazole, pyrazine, pyrimidine, etc.
The 3- to 8-membered, saturated, heterocyclic and monocyclic rings containing 1 to 4 nitrogen atoms include, for example, pyrrolidine, piperidine, imidazolidine, pyrazolidine and piperazine.
The 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing an oxygen atom include, for example, furan and pyran.
The 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing one or two sulfur atoms include, for example, thiophene, dihydrodithiin and dihydrodithion.
The 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two oxygen atoms include, for example, oxazole, oxadiazole and isoxazole.
The 3- to 8-membered, saturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two oxygen atoms include, for example, morpholine and oxazolidine.
The 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two sulfur atoms include, for example, thiazole, isothiazole and thiadiazole.
The 3- to 8-membered, saturated, heterocyclic and monocyclic rings containing 1 to 3 nitrogen atoms and one or two sulfur atoms include, for example, thiazolidine.
The 3- to 8-membered, unsaturated, heterocyclic and monocyclic rings containing an oxygen atom and one or two sulfur atoms include, for example, dihydrooxathiin.
The polycyclic heterocyclic ring includes, for example, unsaturated fused heterocyclic rings containing 1 to 4 nitrogen atoms, unsaturated fused heterocyclic rings containing 1 to 3 nitrogen atoms and one or two oxygen atoms, unsaturated fused heterocyclic rings containing 1 to 3 nitrogen atoms and one or two sulfur atoms, unsaturated fused heterocyclic rings containing one or two oxygen atoms, unsaturated fused heterocyclic rings containing an oxygen atom and one or two sulfur atoms, and unsaturated fused heterocyclic rings containing one or two sulfur atoms.
The unsaturated fused heterocyclic rings containing 1 to 4 nitrogen atoms include, for example, indole, isoindole, indoline, quinoline, isoquinoline, quinolizine, indazole, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, purine, pteridine, phenazine, carboline, phenanthridine, acridine, indoline, isoindoline, 1,2-dihydroisoquinoline, benzimidazole, imidazopyridine, benzotriazole, tetrahydroimidazopyridine, benz[b]azepine, benz[cd]indole, cyclohepta[cd]indole, pyrrolo[3,2,1-ij]quinoline, cyclohexa[b]pyridine, cyclohepta[b]pyridine, pyrrolo[1,2,3-de]quinoxaline, pyrrolo[3,2,1-hi]indole, pyrrolo[3,2,1-jk][1]-benzazepine, pyrrolo[3,2,1-kl][1]benzazocine and pyrrolo[3,2,1-kl]benzo-[e][1,4]diazocine. Preferable examples thereof are indole, quinoline, isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, indoline, benzimidazole, 1,2-dihydroisoquinoline, benz[b]azepine, benz[cd]indole, cyclohepta[cd]indole, cyclohexa[b]pyridine, cyclohepta[b]pyridine, pyrrolo[3,2,1-ij]quinoline, pyrrolo[1,2,3-de]quinoxaline, pyrrolo[3,2,1-hi]indole, pyrrolo[3,2,1-jk][1]benzazepine, pyrrolo[3,2,1-kl][1]-benzazocine, and pyrrolo[3,2,1-kl]benzo[e][1,4]-diazocine. More preferable examples thereof are indole, 1,2-dihydroisoquinoline, benz[b]azepine, benz[cd]indole, cyclohepta[cd]indole, cyclohexa[b]pyridine, cyclohepta[b]pyridine, pyrrolo[3,2,1-jk][1]benzazepine, pyrrolo[3,2,1-kl][1]benzazocine, and pyrrolo[3,2,1-kl]benzo[e][1,4]diazocine.
The unsaturated fused heterocyclic rings containing 1 to 3 nitrogen atoms and one or two oxygen atoms include, for example, benzoxazole, benzoxadiazole, phenoxazine, pyrrolo[1,2,3-de][1,4]benzoxazine, pyrrolo[2,1-c][1,4]benzoxazine, and pyrrolo[3,2,1-kl]benz[e][4,1]oxazocine. Preferable examples thereof are benzoxazole, pyrrolo[1,2,3-de][1,4]benzoxazine, pyrrolo[2,1-c][1,4]benzoxazine and pyrrolo[3,2,1-kl]benz[e][4,1]oxazocine.
The unsaturated fused heterocyclic rings containing 1 to 3 nitrogen atoms and one or two sulfur atoms include, for example, benzothiazole, benzothiadiazole, 1,4-benzothiazine and phenothiazine. Preferable examples thereof are benzothiazole and 1,4-benzothiazine.
The unsaturated fused heterocyclic rings containing one or two oxygen atoms include, for example, benzofuran, dihydrobenzofuran, chromene, isobenzofuran, xanthene, isochroman, chroman and benz[b]oxepine. Preferable examples thereof are benzofuran, benz[b]oxepine, etc.
The unsaturated fused heterocyclic rings containing an oxygen atom and one or two sulfur atoms include, for example, 1,4-benzoxathiin, phenoxathiin, etc.
The unsaturated fused heterocyclic rings containing one or two sulfur atoms include, for example, benzothiophene, benzothiin, benzothiopyran, thiochroman and thianthrene. Preferable examples thereof are benzothiophene, benzothiopyran and thiochroman.
Each of the benzene ring, fused polycyclic hydrocarbon ring, monocyclic heterocyclic ring and polycyclic heterocyclic ring may have one or more substituents which may be the same or different. The substituents include, for example, hydrogen atom, substituted or unsubstituted alkyl groups, substituted or unsubstituted alkenyl groups, substituted or unsubstituted alkynyl groups, substituted or unsubstituted cycloalkyl groups, substituted or unsubstituted cycloalkenyl groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted naphthyl groups, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted acyl groups, carboxyl group, halogen atoms, nitro group and groups represented by the formulas xe2x80x94CN, xe2x80x94OR14, xe2x80x94N(R15)R16, 
(wherein Axe2x80x2 is an oxygen atom, xe2x80x94S(O)nxe2x80x94 or xe2x80x94N(R21)xe2x80x94, m is an integer of 0, 1 or 2, R12 and R21 are independently a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a phenyl group, a naphthyl group, a heterocyclic group or an acyl group, and the ring is a 3- to 8-membered saturated heterocyclic group comprising a nitrogen atom and carbon atoms), and xe2x80x94S(O)nR13.
R13 and R13a are independently a hydroxyl group, a substituted or unsubstituted alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group or a substituted or unsubstituted heterocyclic group.
R15, R6, R17 and R18 are independently a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted cycloalkenyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted acyl group, or R15 and R16, or R17 and R18 may bind to each other to form, together with the nitrogen atom to which they are bonded, a 5- to 7-membered saturated cyclic amino group which may contain other heteroatom(s) in the ring and may be substituted by one or more substituted or unsubstituted alkyl groups, hydroxyl groups or xe2x80x94OR14b groups.
R14, R14a and R14b are independently a hydrogen atom, an alkyl group, a cycloalkyl group, a cycloalkenyl group, a phenyl group, a naphthyl group, a heterocyclic group or xe2x80x94SO3H.
For each of R15, R16, R17 and R18, the substituted alkyl group has one or more substituents which may be the same or different. The substituted alkyl group includes, for example, alkyl groups of 1 to 5 carbon atoms substituted by a cycloalkyl group of 3 to 6 carbon atoms, polyhaloalkyl groups of 1 to 5 carbon atoms, hydroxyalkyl groups of 1 to 6 carbon atoms, alkoxyalkyl groups of 2 to 6 carbon atoms, cyanoalkyl groups of 2 to 6 carbon atoms, carboxyalkyl groups of 2 to 6 carbon atoms, alkoxycarbonylalkyl groups of 3 to 8 carbon atoms, alkanoylalkyl groups of 3 to 8 carbon atoms, aroylalkyl groups of 16 or less carbon atoms, phenyl- or naphthyl-C1xcx9cC5 alkyl groups, carbamoyl-C1xcx9cC3 alkyl groups which may have one or two C1xcx9cC3 alkyl groups as a substituent(s) on the nitrogen atom, amino-C1xcx9cC5 alkyl groups which may have one or two C1xcx9cC3 alkyl or C7xcx9cC11 aralkyl groups as a substituent(s) on the nitrogen atom, and 5- to 7-membered saturated cyclic amino-C1xcx9cC3 alkyl groups.
In the present specification, unless otherwise specified, each of phenyl group, naphthyl group, a fused polycyclic hydrocarbon group, heterocyclic groups (a monocyclic heterocyclic group and a polycyclic heterocyclic group), an aroyl group, a saturated heterocyclic ring-carbonyl group and a heterocyclic aromatic acyl group may have one or more substituents which may be the same or different. The substituents include, for example, alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, saturated heterocyclic groups, phenyl group, naphthyl group, heterocyclic groups, acyl groups, carboxyl group, halogen atoms and nitro group, etc.
Each of the cycloalkyl groups, cycloalkenyl groups and cycloalkanecarbonyl groups may have 1 to 4 substituents which may be the same or different. The substituents include, for example, alkyl groups, substituted alkyl groups, hydroxyl group, and groups represented by the formula xe2x80x94OR34.
As the group represented by R34, there may be exemplified the same groups as those exemplified as the group represented by R4.
As the alkyl groups, there may be exemplified linear or branched alkyl groups of 8 or less carbon atoms, such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, octyl, etc.
As the cycloalkyl groups, there may be exemplified 3- to 8-membered cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopentyl, 3-methylcyclopentyl, 2-methylcyclohexyl, 3-methylcyclohexyl, 4-methylcyclohexyl, 2-hydroxycyclopentyl, 3-hydroxycyclopentyl, 2-hydroxycyclohexyl, 3-hydroxycyclohexyl, 4-hydroxycyclohexyl, 2-(hydroxymethyl)cyclopentyl, 3-(hydroxymethyl)cyclopentyl, 2-(hydroxymethyl)cyclohexyl, 3-(hydroxymethyl)cyclohexyl, 4-(hydroxymethyl)cyclohexyl, 2-(aminomethyl)cyclopentyl, 3-(aminomethyl)cyclopentyl, 2-(aminomethyl)cyclohexyl, 3-(aminomethyl)cyclohexyl, 4-(aminomethyl)cyclohexyl, 2-(methoxymethyl)cyclopentyl, 3-(methoxymethyl)cyclopentyl, 2-(methoxymethyl)cyclohexyl, 3-(methoxymethyl)cyclohexyl, 4-(methoxymethyl)cyclohexyl, etc.
The term xe2x80x9ccycloalkane ringxe2x80x9d in the definition of A and E means a divalent group formed by the conversion of two of the hydrogen atoms of a cycloalkane ring to direct links. Specific examples thereof are 3- to 8-membered cycloalkane rings. More specific examples thereof are divalent groups formed by the conversion of one of the hydrogen atoms of the above-exemplified cycloalkyl group to a direct link.
As the cycloalkenyl groups, there may be exemplified 3- to 8-membered cycloalkenyl groups having a double bond, such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, etc.
As the alkenyl groups, there may be exemplified those having 6 or less carbon atoms, such as vinyl, allyl, propenyl, 2-propenyl, butenyl, pentenyl, hexenyl, etc.
As the alkynyl groups, there may be exemplified those having 6 or less carbon atoms, such as ethynyl, propargyl, butynyl, pentynyl, etc.
The halogen atoms include, for example, iodine, fluorine, chlorine and bromine atoms.
The acyl groups include, for example, formyl group; alkanoyl groups of 2 to 6 carbon atoms, such as acetyl, propanoyl, etc.; cycloalkanecarbonyl groups of 4 to 7 carbon atoms, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, etc.; cycloalkenecarbonyl groups of 3 to 6 carbon atoms, such as. cyclopentenecarbonyl, cyclohexenecarbonyl, etc.; aroyl groups of 6 to 10 carbon atoms, such as benzoyl, toluoyl, naphthoyl, etc.; saturated heterocyclic ring-carbonyl groups having a 5- or 6-membered saturated heterocyclic ring containing one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, for example, 2-piperidinecarbonyl, 3-morpholinecarbonyl, etc.; and heteroaromatic acyl groups having a 5- or 6-membered heteroaromatic ring containing one or two heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, for example, furoyl, thenoyl, nicotinoyl, isonicotinoyl, etc.
The substituted alkyl group may have one or more substituents which may be the same or different. The substituents include halogen atoms, hydroxyl group, alkoxy groups, cycloalkyl groups, cyano group, carboxyl group, acyl groups, substituted or unsubstituted phenyl groups, substituted or unsubstituted naphthyl groups, substituted or unsubstituted heterocyclic groups, oxo group, thioxo group, and groups represented by the formula xe2x80x94CONRpRq (wherein Rp and Rq are independently a hydrogen atom or an alkyl group, or Rp and Rq bind to each other to form a 5- to 7-membered cyclic amino group which may contain other heteroatom(s) in the ring), xe2x80x94SO2R33, xe2x80x94SO2N(R35)R36, xe2x80x94N(R35) R36 or 
wherein Rxe2x80x3 is a hydrogen atom, an alkyl group or a substituted alkyl group, the ring is a 3- to 8-membered saturated heterocyclic group comprising a nitrogen atom and carbon atoms, and the substituent of the substituted alkyl group includes halogen atoms, hydroxyl group, alkoxy groups, cycloalkyl groups, cyano group, carboxyl group, acyl groups, phenyl group, naphthyl group, heterocyclic groups, oxo group and thioxo group.
As R331 R35 and R36, there may be exemplified the same groups as those exemplified above as R13, R15 and R16, respectively.
Such a substituted alkyl group includes, for example, alkyl groups of 1 to 5 carbon atoms substituted by a cycloalkyl group of 3 to 6 carbon atoms; polyhaloalkyl groups of 1 to 5 carbon atoms; hydroxyalkyl groups of 1 to 6 carbon atoms; alkoxyalkyl groups of 2 to 6 carbon atoms; cyanoalkyl groups of 2 to 6 carbon atoms; carboxyalkyl groups of 2 to 6 carbon atoms; alkoxycarbonylalkyl groups of 3 to 8 carbon atoms; alkanoylalkyl groups of 3 to 8 carbon atoms; aroylalkyl groups of 16 or less carbon atoms; substituted or unsubstituted phenyl- or naphthyl-C1xcx9cC5 alkyl groups; carbamoyl-C1xcx9cC3 alkyl groups which may have one or two C1xcx9cC3 alkyl groups as a substituent(s) on the nitrogen atom; amino-C1xcx9cC5 alkyl groups which may have one or two C1xcx9cC3 alkyl or C7xcx9cC11 aralkyl groups as a substituent(s) on the nitrogen atom; and 5- to 7-membered saturated cyclic amino-C1xcx9cC3 alkyl groups.
Typical examples of the substituted alkyl group are polyhaloalkyl groups of 1 to 3 carbon atoms, such as trifluoromethyl, trifluoroethyl, trichloromethyl, etc.; hydroxyalkyl groups of 1 to 6 carbon atoms, such as hydroxymethyl, hydroxyethyl, 1-hydroxyethyl, etc.; aminoalkyl groups of 1 to 5 carbon atoms, such as aminomethyl, aminoethyl, 1-aminoethyl, etc.; alkoxyalkyl groups of 1 to 6 carbon atoms, such as methoxyethyl, ethoxyethyl, methoxypropyl, etc.; carboxyalkyl groups of 2 to 6 carbon atoms, such as carboxyethyl, carboxypropyl, etc.; alkoxycarbonylalkyl groups of 3 to 7 carbon atoms, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, etc.; phenyl- or naphthyl-C1xcx9cC5 alkyl group (which may have in the phenyl or naphthyl portion a substituent such as a C1xcx9cC3 alkyl group, halogen atom, nitro group, amino group, hydroxyl group, C1xcx9cC3 alkoxy group or the like) such as benzyl, phenylethyl, phenylpropyl, phenylbutyl, 1- or 2-naphthylmethyl, etc.; carbamoyl-C1xcx9cC3 alkyl groups which may have one or two C1xcx9cC3 alkyl groups as a substituent(s) on the nitrogen atom, for example, carbamoylmethyl, carbamoylethyl, dimethylcarbamoylmethyl, etc.; amino-C1xcx9cC5 alkyl groups which may have one or two C1xcx9cC3 alkyl or C7xcx9cC11 aralkyl groups as a substituent(s) on the nitrogen atom, for example, aminoethyl, aminopropyl, dimethylaminoethyl, dimethylaminopropyl, dimethylaminoethyl, N-methyl-N-benzylaminoethyl, etc.; and 5- to 7-membered saturated cyclic amino-C1xcx9cC3 alkyl groups such as 1-pyrrolidinylethyl, piperidinoethyl, etc. For R5, R6, R15, R16, R7, R8, R17 and R18, phenyl-C1xcx9cC5 alkyl groups such as phenylethyl and the like may be exemplified as the substituted alkyl group.
As the substituent of each of the substituted alkenyl group, the substituted alkynyl group and the substituted alkanoyl group, there may be exemplified the same groups as those exemplified above as the substituent of the substituted alkyl group. These substituted groups also may have one or more substituents which may be the same or different.
As the aralkyl group, alkyl groups substituted by a phenyl group or a fused polycyclic hydrocarbon ring group may be exemplified.
Oxygen atom, nitrogen atom and sulfur atom may be exemplified as the heteroatom(s) of the 5- to 7-membered saturated cyclic amino group which R5 and R6; R15 and R16; R7 and R8; R17 and R18; or Rp and Rq form together with the nitrogen atom to which they are bonded, by binding to each other and which may contain other heteroatom(s) in the ring. Specific examples of the 5- to 7-membered saturated cyclic amino group are 5- to 7-membered ring groups containing 1 to 3 nitrogen atoms and 5- to 7-membered ring groups containing a nitrogen atom and an oxygen atom. More specific examples thereof are 1-pyrrolidinyl, 1-piperidino, 1-piperazinyl, morpholino, 1-(4-methyl)piperazinyl, etc.
As the group represented by the formula xe2x80x94S(O)2R3, xe2x80x94S(O)2R3a, xe2x80x94S(O)2R13 or xe2x80x94S(O)2R13a, there may be exemplified alkylsulfonyl groups of 8 or less carbon atoms, such as methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, etc. As the group represented by the formula xe2x80x94S(O)nR3, there may be exemplified the above-exemplified groups, corresponding alkylsulfinyl or alkylthio groups, and sulfo group.
Each of the lower alkylene group, the alkenylene group and the alkynylene group may have one or more substituents which may be the same or different. The substituents include, for example, halogen atoms, alkyl groups, substituted alkyl groups, cycloalkyl groups, cycloalkenyl groups, saturated heterocyclic groups, carboxyl group, alkoxycarbonyl groups, phenyl group, naphthyl group, heterocyclic groups, and groups represented by the formula xe2x80x94CON(R45) R46.
As R45 and R46, there may be exemplified the same groups as those exemplified above as R15 and R16.
As the lower alkylene group, there may be exemplified alkylene groups of 10 or less carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, etc.
As the group represented by the formula: 
there may be exemplified groups represented by the following formulas: 
Preferable examples thereof are (piperidin-3-yl)oxy, (piperidin-4-yl)oxy, (1-methylpiperidin-3-yl)oxy, (1-methylpiperidin-4-yl)oxy, (pyrrolidin-3-yl)oxy, (1-methylpyrrolidin-3-yl)oxy, (piperidin-3-yl)thio, (piperidin-4-yl)thio, (1-methylpiperidin-3-yl)thio, (1-methylpiperidin-4-yl)thio, (pyrrolidin-3-yl)thio, (1-methylpyrrolidin-2-yl)thio, (piperidin-3-yl)amino, (piperidin-4-yl)amino, (1-methylpiperidin-3-yl)amino, (1-methylpiperidin-4-yl) amino, (pyrrolidin-3-yl) amino and (1-methylpyrrolidin-3-yl)amino.
The present inventive compound can be synthesized, for example, by any of the following processes.
(A) The present inventive compound can be synthesized by reacting a compound of the formula (2): 
wherein Y, G, A, R and E are as defined above, and L is a hydroxyl group or a leaving group replaceable by a nucleophilic reagent, with guanidine to form a guanidinocarbonyl group (a xe2x80x94C(xe2x95x90O)NHC(xe2x95x90NH)NH2 group), to obtain a compound of the formula (1): 
wherein Y, G, A, R and E are as defined above, and if necessary, converting this product to a prodrug thereof or a pharmaceutically acceptable salt of said product or prodrug.
The leaving group replaceable by a nucleophilic reagent includes, for example, halogen atoms (e.g. fluorine, chlorine and bromine), lower alkoxy groups (e.g. methoxy and ethoxy), aralkyloxy groups (e.g. benzyloxy group), aryloxy groups (e.g. phenoxy group), and groups formed by a condensing agent and a compound of the formula (2) in which L is a hydroxyl group. A process for producing the carboxylic acid or reactive derivative thereof of the formula (2) in which L is any of the above-exemplified groups is concretely explained below.
As the carboxylic acid reactive derivative of the formula (2), there may be exemplified acid halides, acid anhydrides (including mixed acid anhydrides) and ester derivatives. Specific examples of the carboxylic acid reactive derivative are acid halides such as acid chlorides and acid bromides; mixed acid anhydrides of an alkyloxycarbonyl chloride (e.g. ethyloxycarbonyl chloride or isobutoxycarbonyl chloride) and an xcex1-polyalkyl-substituted carboxylic acid chloride (e.g. 2-ethyl-n-butyryl chloride or trimethylacetyl chloride); and ester derivatives such as activated esters (e.g. p-nitrophenyl esters, N-hydroxysuccinimide esters and pentafluorophenyl esters) and common esters (e.g. methyl esters and ethyl esters). Such a carboxylic acid reactive derivative can easily be obtained from a corresponding carboxylic acid according to a conventional method.
When guanidine is reacted with the acid halide or the acid anhydride (including the mixed acid anhydride), the reaction may be carried out in a solvent in the presence of a base or excess guanidine with cooling or at room temperature. As the base, there may be exemplified inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, etc.; and organic bases such as triethylamine, pyridine, etc. As the solvent, there may be exemplified aromatic hydrocarbon solvents such as benzene, toluene, xylene, etc.; ether solvents such as tetrahydrofuran, 1,4-dioxane, etc.; halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, etc.; amide solvents such as dimethylformamide, dimethylacetamide, etc.; basic solvents such as pyridine, etc.; and mixed solvents thereof.
When guanidine is reacted with the ester derivative, the reaction is carried out in a solvent in the presence of an equimolar or excess amount of guanidine with cooling or heating. When the ester derivative is an activated ester, the reaction is preferably carried out, for example, in an ether solvent (e.g. tetrahydrofuran, 1,2-dimethoxyethane or dioxane), an ester solvent (e.g. ethyl acetate), dimethylformamide, or a mixed solvent thereof. When the ester derivative is other than activated esters, the reaction is preferably carried out, for example, in an alcohol solvent (e.g. methanol, ethanol or isopropanol), an ether solvent (e.g. tetrahydrofuran, 1,2-dimethoxyethane or dioxane), dimethylformamide, or a mixed solvent thereof. After the solvent is distilled off, the residue may be heated for a short time at about 130xc2x0 C. if necessary.
When there is used a compound of the formula (2) in which L is a hydroxyl group, a compound of the formula (1) can be obtained preferably by reacting the compound of the formula (2) with guanidine in an inert solvent in the presence of a condensing agent at room temperature or with heating.
The reaction is preferably carried out in the presence of a condensing agent [e.g. dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (WSC), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), diphenylphosphonylazide (DPPA), or N,N-carbonyldiimidazole (Angew. Chem. Int. Ed. Engl., Vol. 1, 351(1962))] and optionally an additive [e.g. N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt) or 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HOObt)] in an aromatic hydrocarbon solvent (e.g. benzene, toluene or xylene), an ether solvent (e.g. tetrahydrofuran or 1,4-dioxane), a halogenated hydrocarbon solvent (e.g. dichloromethane, chloroform or 1,2-dichloroethane), an amide solvent (e.g. dimethylformamide or dimethylacetamide), a basic solvent (e.g. pyridine), or a mixed solvent thereof.
(B) A compound of the formula (1) in which G is a group represented by the formula xe2x80x94Oxe2x80x94 or xe2x80x94N(R11)xe2x80x94, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug can be synthesized by reacting a compound of the formula (3): 
wherein A, R and E are as defined above, and G is a group represented by the formula xe2x80x94Oxe2x80x94 or xe2x80x94N(R11)xe2x80x94 wherein R11 is as defined above, with sulfur trioxide or a complex thereof to form a sulfo group (a xe2x80x94SO3H group) on the group G, to obtain a compound of the formula (12): 
wherein A, R and E are as defined above, and G is as defined above, and if necessary, converting this product to a prodrug thereof or a pharmaceutically acceptable salt of said product or prodrug.
The reaction is carried out as follows: the compound of the formula (3) is reacted with sulfur trioxide (SO3) or a complex thereof (e.g. a sulfur trioxide-pyridine complex, a sulfur trioxide-dioxane complex, or a sulfur trioxidetrimethylamine complex) in a solvent inert with respect to the reaction (e.g. a halogenated hydrocarbon solvent such as chloroform, methylene chloride or the like, sulfuric acid, pyridine or triethylamine) usually at xe2x88x9230xc2x0 C. to the boiling point of the solvent, preferably at 0xc2x0 C. to room temperature.
(A-2) The compound of the formula (2) is well known or may be produced by a combination of well-known processes. It may be produced, for example, by the processes disclosed in the above-mentioned prior art references and the like.
For example, a compound of the formula (2) in which Y is xe2x80x94SO3H may be produced by reacting a compound of the formula (4): 
wherein A, R and E are as defined above and G is a group represented by the formula xe2x80x94Oxe2x80x94 or xe2x80x94N(R11)xe2x80x94 wherein R11 is as defined above, with sulfur trioxide or a complex thereof by a method known in literature (for instance, Organic Functional Group Preparations, second edition; Wasserman, H. H.; Academic Press: London, 1983; Vol. 1, pp. 619-639) or in the same manner as in the above item (B).
As conditions, reagents and the like for the reaction with sulfur trioxide or a complex thereof, there may be exemplified the same conditions, reagents and the like as those described in the above item (B).
(A-3) A compound of the formula (2) in which Y is a group represented by the formula: 
may be produced, for example, by introducing the group represented by the above formula or a group formed by protecting the functional groups of said group either into the compound disclosed in any of the above-mentioned prior art references and the like or in the production process of this compound by a method known in literature (for instance, Shin Jikken Kagaku Koza (New Experimental Chemistry), Vol. 14, xe2x80x9cSynthesis and Reaction of Organic Compounds (V)xe2x80x9d, pp. 2422-2429), and carrying out deprotection at a proper stage.
For example, a compound of the formula (2) in which G is a group represented by the formula xe2x80x94Oxe2x80x94 or xe2x80x94N(R11)xe2x80x94 and Y is a group represented by the formula: 
may be produced by reacting a compound of the formula (4): 
wherein A, R and E are as defined above and G is a group represented by the formula xe2x80x94Oxe2x80x94 or xe2x80x94N(R11)xe2x80x94 wherein R11 is as defined above, with a reactive derivative of a compound of the formula (6): 
The compound of the formula (6) includes D-glucuronic acid, L-iduronic acid, L-glucuronic acid, D-mannuronic acid, D-galacturonic acid, etc. Said compound is not limited to these natural uronic acids.
The reaction with the reactive derivative of the compound of the formula (6) may be carried out, for example, as follows: the compound of the formula (4) is reacted with a reactive derivative obtained by protecting the hydroxyl groups and carboxyl group of the above-exemplified compound (a form in which the hydroxyl group is protected includes acetyloxy, benzyloxy, etc., and a form in which the carboxyl group is protected includes a benzyl ester, etc.), for example, an imidate derivative: 
(for instance, imidate derivative of glucuronic acid) (the hydroxyl groups and carboxyl group of the imidate derivative are protected with protective groups (see the above)) according to the so-called imidate method (described, for example, in Helvetica Chimica Acta, 79, 1757-1784 (1996)) in a solvent inert with respect to the reaction (e.g. a halogenated hydrocarbon solvent such as chloroform, methylene chloride or the like) in the presence of a Lewis acid (e.g. a boron trifluoridediethyl ether complex) usually at xe2x88x9230xc2x0 C. to the boiling point of the solvent, preferably at 0xc2x0 C. to room temperature.
When the carboxyl group contained in the imidate derivative of compound of the formula (6) is protected, the deprotection of the carboxyl group is preferably carried out at a stage prior to the next step, i.e., the formation of a guanidinocarbonyl group described in the above item (A). When the compound of the formula (4) has a reactive group such as hydroxyl group or amino group in the side chain, the reactive group may be previously protected with a suitable protective group if necessary, and the protective group may be removed after carrying out the reaction.
(B-2) The compound of the formula (3) may be produced by reacting a compound of the formula (4): 
wherein A, R and E are as defined above and G is a group represented by the formula xe2x80x94Oxe2x80x94 or xe2x80x94N(R11)xe2x80x94 wherein R11 is as defined above, with guanidine as in the above item (A) to form a guanidinocarbonyl group (a xe2x80x94C(xe2x95x90O)NHC(xe2x95x90NH)NH2 group).
As conditions, reagents and the like for the reaction with guanidine, there may be exemplified the same conditions, reagents and the like as those described in the above item (A).
(C) A compound of the formula (1) in which Y is a group represented by the formula xe2x80x94PO3H2 may be produced, for example, by the following process.
First, a well-known compound or a compound of the formula (5): 
wherein A, R, E and L are as defined above and W is a halogen atom, a substituted or unsubstituted alkylsulfonyloxy group or a substituted or unsubstituted arylsulfonyloxy group, which may be obtained from a well-known compound by a process known in literature (for example, the process described in the above item (B)), is reacted with a phosphorous acid triester of the formula P(OR41)(OR42)(OR43) or a phosphorous acid diester of the formula HP(xe2x95x90O)(O R42) (OR43) by a process known in literature (for example, Jikken Kagaku Koza (Experimental Chemistry), 4th edition, Vol. 24, Organic Synthesis VI, pp. 248-249) to form a phosphoric acid diester group (a xe2x80x94P(xe2x95x90O)(O R42) (OR43) group) at the position of A. In the above formulas, R41, R42 and R43 are independently a substituted or unsubstituted alkyl group. Thus, there is obtained a compound of the formula (6): 
wherein A, R, E, L, R42 and R43 are as defined above.
The reaction with the phosphorous acid triester is usually carried out without solvent at a reaction temperature of 100xc2x0 C. to 200xc2x0 C. for a reaction time of 1 to 5 hours. The reaction with the phosphorous acid diester is usually carried out in an ether solvent (e.g. tetrahydrofuran) or dimethylformamide in the presence of a base (e.g. potassium tertbutoxide) at a reaction temperature of xe2x88x9220xc2x0 C. to 30xc2x0 C. for a reaction time of 1 to 5 hours.
Then, the compound of the formula (6) is reacted with guanidine as in the above item (A) to form a guanidinocarbonyl group (a xe2x80x94C(xe2x95x90O)NHC(xe2x95x90NH)NH2 group), whereby there is obtained a compound of the formula (7): 
wherein A, R, E, R42 and R43 are as defined above. As the reaction conditions, the conditions described in the above item (A) may be exemplified.
Subsequently, a compound of the formula (8): 
wherein A, R and E are as defined above, may be produced by removing R42 and R43 from the compound of the formula (7).
The reaction may be carried out in a halogen-containing solvent (e.g. dichloromethane), acetonitrile or dimethylformamide at a reaction temperature of 20xc2x0 C. to 100xc2x0 C. for 1 to 3 days (these reaction conditions are described, for example, in Synthesis 485 (1993)).
A compound of the formula (9): 
wherein R42, A, R and E are as defined above, may be produced by removing only R43 selectively. For example, when a benzyl group is used as R43, the compound of the formula (9) may be produced by a conventional benzyl group removing reaction (for example, the method described in Protective Groups in Organic Synthesis, JOHN WILLEY and SONS, 1991).
(D) Each of the compounds of the formula (4) and the formula (3) is well known or may be produced by a combination of well-known processes. It may be produced, for example, by the processes disclosed in the above-mentioned prior art references and the like.
Each of these compounds may be produced by introducing a guanidinocarbonyl group or a group represented by the formula xe2x80x94SO3H or 
and synthesizing a basic skeleton, by the above-mentioned method in the course of the production process disclosed in any of the above-mentioned prior art references and the like.
For example, a compound of the formula (4) in which L is a hydroxyl group can easily be derived from a corresponding ester of the formula (4) in which L=ORb wherein Rb is a lower alkyl group (e.g. methyl or ethyl), an aralkyl group (e.g. benzyl group) or an aryl group (e.g. phenyl), by conventional hydrolysis. A compound of the formula (4) in which L is a leaving group replaceable by a nucleophilic reagent may be synthesized from a compound of the formula (4) in which L is a hydroxyl group, by a conventional method.
When the starting compound in the reaction in each of the production processes described above has a reactive group such as hydroxyl group, amino group or carboxyl group, the reactive group is previously protected with a suitable protective group if necessary, and the protective group is removed after carrying out the reaction or carrying out several reactions, whereby a desired compound may be obtained. As the protective group for the hydroxyl group, amino group or carboxyl group, protective groups conventionally used in the field of organic synthetic chemistry may be used. The introduction and removal of such a protective group may be carried out by a conventional method (for example, Protective Groups in Organic Synthesis, JOHN WILLEY and SONS, 1991).
For example, the protective group for the hydroxyl group includes methoxymethyl group, tetrahydropyranyl group, etc. The protective group for the amino group includes tert-butoxycarbonyl group, etc. Such a protective group for the hydroxyl group may be removed by reaction in a solvent such as aqueous methanol, aqueous ethanol or aqueous tetrahydrofuran in the presence of an acid such as hydrochloric acid, sulfuric acid or acetic acid. The protective group for the amino group may be removed by reaction in a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform or aqueous methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid.
As an enbodyment in which the carboxyl group is protected, there may be exemplified tert-butyl esters, orthoesters and acid amides. The protective group used for this protection is removed as follows. In the case of the tert-butyl esters, the removal is carried out, for example, by reaction in an aqueous solvent in the presence of hydrochloric acid. In the case of the orthoesters, the removal is carried out, for example, by treatment with an acid and then an alkali such as sodium hydroxide in a solvent such as aqueous methanol, aqueous tetrahydrofuran or aqueous 1,2-dimethoxyethane. In the case of the acid amides, the removal may be carried out, for example, by reaction in a solvent such as water, aqueous methanol or aqueous tetrahydrofuran in the presence of an acid such as hydrochloric acid or sulfuric acid.
The compound of the formula (1) has the acylguanidine moiety shown in the above formula (1) and has tautomers. In detail, there are a tautomer [xe2x80x94C(xe2x95x90O)Nxe2x95x90C(NH2)2] whose acylguanidine moiety is diaminomethyleneamino, and another tautomer [xe2x80x94C(xe2x95x90O)NHxe2x80x94C(xe2x95x90NH)NH2] whose acylguanidine moiety is aminoiminomethylamino. These tautomers are different only in state and are the same compound. Therefore, the present invention includes both of the tautomers.
The compound of the formula (1) includes those having an optical center of asymmetry. The compound having an optical center of asymmetry may be obtained as a racemic modification, or it may be obtained as an optically active substance when an optically active starting material is used. If necessary, the recemic modification obtained may be physically or chemically resolved into optical antipodes by a conventional method. Preferably, diastereomers are formed from the racemic mixture by a reaction using a reagent for optical resolution. The diastereomers different in form may be resolved by a conventional method such as fractional crystallization.
As the xe2x80x9cprodrugxe2x80x9d, there may be exemplified those which are easily hydrolyzed in a living body to regenerate the compound of the formula (1). For example, when the compound of the formula (1) has a carboxyl group, examples of the prodrug are compounds obtained by converting the carboxyl group to an alkoxycarbonyl group, an alkylthiocarbonyl group or an alkylaminocarbonyl group.
For example, when the compound of the formula (1) has an amino group, examples of the prodrug are compounds obtained by converting the amino group to an alkanoylamino group by substitution by the alkanoyl group, compounds obtained by converting the amino group to an alkoxycarbonylamino group by substitution by the alkoxycarbonyl group, and compounds obtained by converting the amino group to an acyloxymethylamino group or hydroxylamine.
For example, when the compound of the formula (1) has a hydroxyl group, examples of the prodrug are compounds obtained by converting the hydroxyl group to an acyloxy group by substitution by the above-exemplified acyl group, and compounds obtained by converting the hydroxyl group to a phosphoric ester or an acyloxymethyloxy group.
For example, when the compound of the formula (1) has a sulfo group, examples of the prodrug are compounds obtained by converting the sulfo group to a sulfonic ester by substitution by an alkyl group.
For example, when the compound of the formula (1) has a phosphono group, examples of the prodrug are compounds obtained by converting the phosphono group to a phosphonic acid monoester or a phosphonic acid diester by substitution by one or two alkyl groups.
Examples of the alkyl portion of the group used for such conversion to the prodrug are the above-exemplified alkyl groups. The alkyl group may be substituted by, for example, an alkoxy group of 1 to 6 carbon atoms. Preferable examples of the group formed for the above conversion to the prodrug are as follows.
(a) For example, in the case of compounds obtained by converting the carboxyl group to an alkoxycarbonyl group, the alkoxycarbonyl group includes, for example, lower (number of carbon atoms: for example, 1 to 6) alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, etc.; lower (number of carbon atoms: for example, 1 to 6) alkoxycarbonyl groups substituted by a lower (number of carbon atoms: for example, 1 to 6) alkoxy group, such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, etc.; lower (number of carbon atoms: for example, 1 to 6) alkoxycarbonyl groups substituted by a lower (number of carbon atoms: for example, 1 to 6) alkoxycarbonyloxy group, such as 1-(ethoxycarbonyloxy)ethyl; (1,3-dihydro-3-oxo-1-isobenzofuranyl)oxycarbonyl; and (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl.
(b) For example, in the case of compounds obtained by converting the sulfo group to an alkoxysulfonyl group, the alkoxysulfonyl group includes lower (number of carbon atoms: for example, 1 to 6) alkoxysulfonyl groups such as methoxysulfonyl, ethoxysulfonyl, etc.; and lower (number of carbon atoms: for example, 1 to 6) alkoxysulfonyl groups substituted by a lower (number of carbon atoms: for example, 1 to 6) alkoxy group, such as methoxymethoxysulfonyl, ethoxymethoxysulfonyl, 2-methoxyethoxysulfonyl, 2-methoxyethoxymethoxysulfonyl, pivaloyloxymethoxysulfonyl, etc.
(c) For example, in the case of compounds obtained by converting the phosphono group to an alkoxyphosphoryl group, the alkoxyphosphoryl group includes lower (number of carbon atoms: for example, 1 to 6) mono- or dialkoxyphosphoryl groups such as methoxy(hydroxy)phosphoryl, ethoxy(hydroxy)phosphoryl, dimethoxyphosphoryl, diethoxyphosphoryl, etc.; and lower (number of carbon atoms: for example, 1 to 6) mono- or dialkoxyphosphoryl groups substituted by a lower (number of carbon atoms: for example, 1 to 6) alkoxy group, such as methoxymethoxy(hydroxy)-phosphoryl, ethoxymethoxy(hydroxy)phosphoryl, 2-methoxyethoxy(hydroxy)phosphoryl, 2-methoxyethoxymethoxy(hydroxy)phosphoryl, pivaloyloxymethoxy(hydroxy)phosphoryl, bis(methoxymethoxy)phosphoryl, bis(ethoxymethoxy)phosphoryl, bis(2-methoxyethoxy)phosphoryl, bis(pivaloyloxymethoxy)phosphoryl, etc.
If necessary, the compound of the formula (1) or the prodrug thereof may be converted to a pharmaceutically acceptable salt. As such a salt, there may be exemplified salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, etc.; salts with organic carboxylic acids such as formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, aspartic acid, glutamic acid, etc.; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid, etc.; alkali metal salts such as sodium salt, potassium salt, etc.; alkaline earth metal salts such as calcium salt, magnesium salt, etc.; ammonium salt; triethylamine salt; pyridine salt; picoline salt; ethanolamine salt; dicyclohexylamine salt; and N,Nxe2x80x2-dibenzylethylenediamine salt.
Each of the compounds of the formula (1), the prodrugs thereof and the pharmaceutically acceptable salts of the compounds or prodrugs may be in the form of an anhydride, hydrate or solvate.
When used as a pharmaceutical composition, the present inventive compound may be orally or parenterally administered. That is, the present inventive compound may be orally administered in a usual dosage form such as powder, granules, tablets, capsules, syrup, suspension or the like, or the present inventive compound may be parenterally administered, for example, by injection of a solution, emulsion or suspension prepared from the present inventive compound. The present inventive compound may be administered rectally in the form of a suppository. The present inventive compound may be formulated into the above-exemplified suitable dosage form by blending the present inventive compound with conventional acceptable adjuvants such as a carrier, excipient, binder, stabilizer and diluent. When the present inventive compound is used in the form of an injection, the injection may contain acceptable additives such as a buffer, solubilizer and tonicity agent. Although the dose and the number of administrations are varied depending on, for example, a disease to be cured, the condition of the disease, age, body weight and administration route, the present inventive compound may be administered to an adult in a dose of usually 0.1 to 2,000 mg, preferably 1 to 200 mg per day in one portion or several portions (for example, 2 to 4 portions).
In the present invention, as more preferable compounds, there may be exemplified compounds represented by the formula: 
wherein Y, G, A and E are as defined above;
Q is a substituted or unsubstituted lower alkylene group (one or more of the xe2x80x94CH2xe2x80x94 groups of said lower alkylene group may be replaced by one or more substituents, respectively, which may be the same or different and are selected from groups represented by the formula xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R31)xe2x80x94 and xe2x80x94C(xe2x95x90O)xe2x80x94 (as R31, there may be exemplified the same groups as those exemplified above as R1), and any two adjacent atoms of said lower alkylene group may form a double bond or a triple bond);
the group represented by the formula xe2x80x94Exe2x80x94C(xe2x95x90O)NHC(xe2x95x90NH)NH2 in each of the above formulas may be bonded to any acceptable position of the indole ring, the group represented by the formula Yxe2x80x94Gxe2x80x94Axe2x80x94 in each of the formulas (31), (32) and (34) may be bonded to any acceptable position of the indole ring, and the group represented by the formula Yxe2x80x94Gxe2x80x94Axe2x80x94 in each of the formulas (33) and (35) may be a substituent on Q, preferably on the carbon atom of Q, prodrugs of said compounds, and pharmaceutically acceptable salts of said compounds and prodrugs.
In the formulas (31) to (35), the polycyclic heterocyclic rings may be substituted by any of the above-exemplified substituents of polycyclic heterocyclic ring, inclusive of the hydrogen atom of the group represented by the formula xe2x80x94NHxe2x80x94 in the ring.
The present invention is more concretely illustrated below with examples and test examples, which should not be construed as limiting the scope of the invention. The nomenclature of compounds shown in the examples mentioned below is not always based on IUPAC.